EP0708771B1 - Benzylaminoquinuclidines en tant qu'antagonistes de substance p - Google Patents

Benzylaminoquinuclidines en tant qu'antagonistes de substance p Download PDF

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EP0708771B1
EP0708771B1 EP94919851A EP94919851A EP0708771B1 EP 0708771 B1 EP0708771 B1 EP 0708771B1 EP 94919851 A EP94919851 A EP 94919851A EP 94919851 A EP94919851 A EP 94919851A EP 0708771 B1 EP0708771 B1 EP 0708771B1
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compound
azabicyclo
diphenylmethyl
octane
alkyl
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EP0708771A1 (fr
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Kunio Satake
Hiroaki Wakabayashi
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Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • This invention relates to novel and useful benzyloxyquinuclidines of interest to those in the field of medical chemistry and chemotherapy. More particularly, it is concerned with a novel series of benzyloxyquinuclidines, including their pharmaceutically acceptable salts and pharmaceutical composition thereof, which are of special value in view of their ability to antagonize substance P (SP).
  • SP substance P
  • these compounds are of use in treating gastrointestinal disorders, central nervous system disorders, allergy, inflammatory diseases, asthma, pain, migraine, emesis, urinary incontinence and angiogenesis in mammalia.
  • Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specially, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in US Pat. 4680283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., J. Med.
  • tachykinin antagonists are useful for allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol., 66, 1361, 1988), immunoregulation (Lotz et al., Science, 241, 1218, 1988; and Kimball et al., J. Immunol., 141, 3564, 1988), vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al., PNAS, 85, 3235, 1988) and senile dementia of the Alzheimer type (Yankner et al., Science, 250, 279, 1990).
  • JP Kokai No. 78354/93 discloses a wide variety of azabicyclic compounds as tachykinin antagonists such as substance P antagonists, including a number of quinuclidine compounds having diarylmethyl and benzyloxy substituents.
  • tachykinin antagonists such as substance P antagonists
  • quinuclidine compounds having diarylmethyl and benzyloxy substituents.
  • none of the individual compounds described in JP Kokai No. 78354/93 (EP-0499313A1) is a 6-diarylmethyl-5-benzyloxyquinuclidine having an additional substituent at the 2- or 3- position.
  • A. M. Mac Leod et al disclose N-acyl-L-tryptophan benzyl ethers as patent substance P antagonists in J. Med. Chem., Vol 36, pp 2044-45, 1993.
  • WO 92/20676 discloses substituted 3-aminoquinuclidines as substance P antagonists for the treatment of inflammatory disorders.
  • the purpose of the present invention is to provide the novel benzyloxyquinuclidines with substance P antagonistic activities.
  • the purpose of the invention is also to provide a composition, which includes a benzyloxyquinuclidine as an active ingredient, in treating of gastrointestinal disorders, central nervous system disorders, allergy, inflammatory diseases, asthma, pain, migraine or emesis in mammalia, especially humans.
  • the inventors made an effort in order to create compounds with substance P antagonistic activity. As a result, they discovered that specific benzyloxyquinuclidines and their pharmaceutically acceptable salts have excellent activity for the treatment of gastrointestinal disorders, central nervous system disorders, allergy, inflammatory diseases, asthma, pain migraine, emesis, urinary incontinence or angiogenesis, based on SP antagonistic activity.
  • the present invention relates to a compound of the chemical formula (I) and its pharmaceutically acceptable salt: wherein X and Y are each hydrogen, halo, C 1 -C 6 alkyl, halosubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl or tri C 1 -C 6 alkylsilyl;
  • the preferred position of the substituent Z-A- on the quinuclidine ring is the 3-position, and the preferred configuration is 3R,4S or 3S,4R. S is preferable for the configuration of both benzyloxy at 5 position and diarylmethyl at 6 position.
  • Preferred compounds of the present invention are those having structure of formula (I) wherein Ar 1 and Ar 2 are phenyl; Z-A- is at the 3-position, A is -CO-; Z is -OH, -OCH 3 , -NR 1 R 2 (wherein R 1 and R 2 are each -H, -CH 3 or -CH 2 CH 3 ), morpholino or NH 2 COCH 2 NH-; X is hydrogen, 3-CH 3 , 3-CF 3 or 3-F; and Y is 5-CH 3 , 5-CF 3 or 5-F.
  • Preferred compounds of the present invention are:
  • the compounds of formula (I) form acid addition salts and these salts are within the scope of this invention.
  • the pharmaceutically acceptable acid addition salts are those formed from acids which form non-toxic acid salts.
  • the present invention includes pharmaceutical compositions for treatment or prevention of a condition selected from the group consisting of inflammatory diseases (e.g, arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, colitis, psychosis, pain, gastroesophageal reflux disease, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic disease such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, rheumatic
  • This invention relates to the therapeutic method which comprises administering to a mammal, especially a human, a therapeutically effective amount of a compound of the formula (I) or its pharmaceutically acceptable salt in order to treat or prevent the above diseases.
  • This invention also provides a compound of the formula: wherein
  • this invention provides a process for preparing the intermediate compounds of formula (II), which comprises the following steps:
  • the present invention also provides another method to prepare the above-mentioned intermediate compounds, which comprises the following steps:
  • the present invention provides a process for preparing a compound of formula (I), which comprises the following steps:
  • novel benzyloxyquinuclidines (I) of this invention may be prepared by a number of synthetic methods well known to those skilled in the art.
  • Route 1 is a method through amidation of 6-diarylmethyl-2(or3)-carboxyquinuclidine-5-one (i) and reduction followed by benzylation.
  • the amide (iv) is easily hydrolised to carboxylic acid (vi).
  • compound (iii) corresponds to the intermediate compound of formula (II) wherein T-A- is C(O)NR 1 R 2 .
  • the transformation from carboxylic acid (i) to amide (ii) can be used by, for example, (EtO) 2 POCN-amine (NHR 1 R 2 ), ClCO 2 Et-NHR 1 R 2 or the condensation method with NHR 1 R 2 using DCC (dicyclohexylcarbodiimide) or WSC (water solble carbodiimide) in the inert solvent such as dimethylformamide (DMF) and tetrahydrofuran (THF).
  • the amidation can be carried out at a temperature of from -78°C to reflux temperature, preferably from -5 to 30°C for 5 minutes to 48 hours, preferably from 60 minutes to 18 hours.
  • the carbonyl group at 5 position is derived to the compound (iii) by reduction.
  • the appropriate reduction agents such as sodium borohydride in methanol in this reduction.
  • LiBEt 3 H in DME for the cis selective reduction and Na in isopropanol for trans selective reduction are convenient respectively.
  • the reduction can be carried out at a temperature of from -78 to 30°C, preferably from -5 to 30°C for 5minutes to 48 hours, preferably from 60 minutes to 2 hours.
  • Benzyl compound (iv) can be obtained by reacting alcohol (iii) with benzyl bromide in the presence of a base.
  • the preferable bases in the benzylation are t. BuOK, NaH, KH, KOH, BuLi, LDA and the like.
  • the crown-ethers such as 18-crown-6 can be added to the reaction if needed.
  • Benzyl chloride, benzyl iodide, benzyl triflate, benzyl mesylate and the like can be used as benzylating agents.
  • the benzylation can be carried out at a temperature of from -78°C to reflux temperature, preferably from -5 to 30°C for 30 minutes to 48hours, preferably from 30 minutes to 4 hours. (wherein all the symbols, except Z is hydroxy, are the same as aobve).
  • Route 2 for preparing the object compound (I) is the chemical modification of the carboxylic acid (vi) which is obtained in Route 1.
  • the -CO 2 H part can be converted to the other ZA groups according to methods wellknown to those skilled the in the art.
  • the carboxylic acid can be also converted to the corresponding ester by a standard procedure such as an acid or base catalyzed esterification in adequate alcohols or methylation by diazomethane.
  • a compound in which Z is (W 1 -(CH 2 ) m -CHR 4 -(CH 2 ) n -NR 3 (wherein all the symbols are the same as already defined) in the side chain Z-CO- on the quinuclidine ring can be synthesized by a various conventional methods for peptide synthesis as described in "Peptide synthesis, the basis and experiments" edited by N. Izumiya, 1985 (Maruzen).
  • those methods include an activated ester method with acid chloride or mixed acid anhydride, and a condensation method employing an appropriate condensing agent which is selected from dicyclohexylcarbodiimide (DCC), water soluble carbodiimide, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, Bop agent (Benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate), diethyl azodicarboxylate-triphenylphosphine, diethylcyanophosphonic acid and diphenylphospholylazide and the like.
  • DCC dicyclohexylcarbodiimide
  • 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline
  • Bop agent Benzotriazol-1-yloxy-tris(dimethyl
  • a reaction-inert solvent such as dichloromethane, THF, dimethylformamide and toluene are suitable in the condensation reaction. If necessary, addition of tertiary amine such as triethylamine can promote the condensation reaction. Furthermore, in order to prevent racemization, employment of N-hydroxy succinimide, N-hydroxybenzotriazole or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine etc. can bring a preferable result in this reaction. In general, the esterification can be carried out at from -78 to reflux temperature, preferably from -5 to 30°C for 5 minutes to 48 hours, preferably from 60 minutes to 18 hours.
  • a suitable protective group can be chosen from a variety of known protective groups such as benzyloxycarbonyl (Cbz), t.-butyloxycarbonyl (Boc) and trialkylsilyl (c.f. T. W. Greene, "Protective Groups in Organic Synthesis", J. Wiley & Sons (1981)).
  • the protecting group is removed by a suitable standard procedure to provide the objective compound.
  • side chain (Z-A-) on the quinuclidine ring is methoxycarbonyl, carbamoyl, ethylaminocarbonyl, N-methoxy-N-methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl, (4-thiamorpholino-4-oxo)carbonyl, (4-thiamorpholino-4,4-dioxo)carbonyl, carboxy, N-(2-carbamoylpyrrolidin-1-yl)carbonyl, N-(1-carbamoylmethyl)carbamoyl, N-(1-carbamoylethyl)carbamoyl, N-(1-carbamoyl-3-methylbutyl)carbamoyl, N-(2-carbamoylethyl)carbamoyl, N-(2-carb
  • Route 1A may be used.
  • Route 1A is a method through reduction of 6-diarylmethyl-2(or 3)-carboxyquinuclidine-5-one (i) or hydrolyzation of compound (iii), and esterification followed by benzylation.
  • the ester (ix) can be easily derived to carboxylic acid (vi).
  • compound (viii) corresponds to the intermediate compound of formula (II) wherein T-A- is -C(O)OR 1 .
  • the reduction of ketone (i) to compound (vii) may be carried out in a similar manner to the reduction of compound (ii) as described in Route 1 above.
  • the reduction may be carried out in the presence of an appropriate reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a reaction-inert solvent such as methanol, ethanol, tetrahydrofuran, methylene chloride or acetic acid.
  • an appropriate reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a reaction-inert solvent such as methanol, ethanol, tetrahydrofuran, methylene chloride or acetic acid.
  • compound (vii) can be also prepared by hydrolyzation of compound (iii).
  • Carboxylic acid (vii) can be converted to the corresponding ester (viii) by a standard procedure as described in Route 2 above.
  • Benzyl compound (ix) can be obtained by reacting ester (viii) with a benzylating agent under similar conditions to those described in Route 1 above.
  • Compound (ix) can be directly obtained by benzylation of Compound (vii) if R 1 is benzyl or substituted benzyl such as alkylbenzyl or alkoxybenzyl. If desired, Compound (ix) can be easily hydrolyzed to obtain compound (vi). Suitable methods for the hydrolyzation are described in T. W. Greene, "Protective Groups in Organic Synthesis", J. Wiley & Sons (1981)).
  • Compound (ix) wherein R 1 is benzyl or the substituted benzyl as mentioned above can be subjected to hydrogenolysis using a metallic catalyst such as palladium on carbon in alcohol such as methanol, ethanol or isopropylalcohol, to obtain Compound (vi).
  • a metallic catalyst such as palladium on carbon in alcohol such as methanol, ethanol or isopropylalcohol
  • reaction used in the above general synthesis can be easily monitored by thin-layer chromatography (TLC).
  • the quinuclidine compounds of this invention all possess at least two asymmetric centers, they are capable of occurring in various stereoisomeric forms or configurations.
  • the compounds can exist in separated (+)- and (-)-optically active forms, as well as in racemic or ( ⁇ )-mixtures thereof.
  • the present invention includes all such forms within its scope.
  • the diastereomers can be obtained by methods well known to those skilled in the art, e.g., by separation of mixtures by fractional crystallization or chromatographic separation, asymmetric synthesis and the like.
  • they may choose any desired isomers, such as optical isomers and diastereomers, or mixtures thereof, from among the objective compounds of the present invention according to their application purpose.
  • quinuclidine compounds of this invention are basic compounds, they are all capable of forming a wide variety of salts with various inorganic and organic acids.
  • the quinuclidine base compound must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the quinuclidine base compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent and thereafter, subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the quinuclidine base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the acid which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned quinuclidine base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1.1'-methylene-bis-(2-hydroxy-3-naphthoate))salts.
  • non-toxic acid addition salts i.e., salts containing pharmaceutically acceptable anions, such
  • the quinuclidine compounds of the invention which have also acidic groups are capable of forming base salts with various pharmaceutically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic quinuclidine derivatives. These particular non-toxic base salts include those derived form such pharmaceutically acceptable cations as sodium, potassium, calcium and magnesium, etc.
  • salts can easily be prepared by treating the aforementioned acidic quinuclidine compounds with an aqueous solution containing the desired pharmaceutically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanoic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum production of yields of the desired final product.
  • the quinuclidine compounds of the formula I exhibit significant substance P receptor-binding activity and therefore, are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of said substance P activity.
  • Such conditions include gastrointestinal disorders such as ulcer and colitis and other like diseases of the gastrointestinal tract, central nervous system disorders such as anxiety and psychosis, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, respiratory diseases such as asthma, allergy, emesis, sunburn, as well as pain in any of the aforesaid conditions, including migraine.
  • these compounds are readily adapted to therapeutic use as substance P antagonists for the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
  • the activity of the compounds of the present invention is determined by their ability to inhibit the binding of substance P at its receptor sites in CHO-cells which reveal NK1 receptor or IM-9 cells employing radioactive ligands.
  • the substance P antagonist activity of the herein described quinuclidine compounds is evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry , 258, 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues or IM-9 cells, thereby affording characteristic IC 50 values for each compound tested. In this test, some preferred compounds indicated low IC 50 values of less than 0.1 nM with respect to inhibition of binding at its receptor.
  • the compounds of the present invention when tested as an antiinflammatory agent, exhibit a significant degree of activity in the mustard oil-induced rat foot edema test [described by F. Lembeck et al., British Journal of pharmacology, 105, 527 (1992)] .
  • the antiinflammatory activity of the compounds of the present invention is demonstrated by a capsaicin-indused plasma extravasation test.
  • antiinflammatory activity is determined as the percent inhibition of plasma protein extravasation in the ureter of male Hartley quinea pigs (weighing 300-350 g) in response to the intraperitoneal injection of capsaicin into anesthetized animals.
  • the compounds of the present invention are dissolved in 0.1% methyl cellulose/water and dosed orally 1h before capsaicin challenge.
  • Evans Blue dye (30 mg/kg) is administered intravenously 5 min before capsaicin challenge. The animals are killed 10min after capsaicin injection and both right and left ureters are removed. The Evans Blue dye is extracted and determined colorimetrically.
  • compounds are considered active if the difference in response between the drug-treated animals and a control group receiving the vehicle alone is statistically significant.
  • the compounds of formula (I) of this invention show surprisingly high activity.
  • the ED 50 of the compound in example 2 was more than 100 times lower than the ED 50 of the non-substituted compound (x) disclosed in JP Kokai 78354/93 (EP-0499313A1) was 2.4 mg/kg.
  • Example 2: Z-A- CO 2 H
  • the anti-psychotic activity of the compounds of the present invention as neuroleptic agents for the control of various psychotic disorders is determined primarily by a study of their ability to suppress substance P-induced hypermotility in rats. This study is carried out by first dosing the rats with a control compound or with an appropriate test compound of the present invention, then injecting the rats with substance P by intracerebral administration via canula and thereafter measuring their individual locomotor response to said stimuli.
  • the radiolabelled quinuclidine compounds of the formula I are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays with the drug in both animal and human. Specific applications in research include radioligand binding assays, autoradiography studies and in vivo binding studies, while specific applications in the diagnostic area include studies of substance P receptor in the human brain, such as up/down regulation in a diseases state, and in vivo binding in the relevant tissues for inflammation, e.g., immune-type cell or cells that are directly involved in inflammatory bowel disorders and the like.
  • the radiolabelled forms of the quinuclidine compounds are the tritium and 14 C-isotopes of substituted benzyloxyquinuclidine in this invention.
  • the quinuclidine compounds of the formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals.
  • these compounds can be administered to humans in doses ranging from about 0.3 mg up to 750 mg per day. Variations will necessarily occur depending upon the weight of the subject being treated, the particular route of administration, the disease state of the subject being treated and the activity of the particular compound chosen.
  • a dosage level that is in the range of from about 0.06 mg to about 2 mg per kg of body weight per day is most desirably employed for treatment or prevention of an inflammatory, pain, and emesis condition in a human subject.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene grycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

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Claims (22)

  1. Composé de formule chimique (I) et ses sels pharmaceutiquement acceptables :
    Figure 00450001
    formule dans laquelle
    X et Y représentent chacun l'hydrogène, un groupe halogéno, alkyle en C1 à C6, alkyle en C1 à C6 halogéno-substitué, alkoxy en C1 à C6, alkylthio en C1 à C6, alkylsulfinyle en C1 à C6, alkylsulfonyle en C1 à C6, ou tri(alkyle en C1 à C6)silyle ;
    Ar1 et Ar2 représentent chacun un groupe aryle ou hétéroaryle, groupe qui est facultativement substitué avec un substituant halogéno ;
    A représente un groupe -CO- ou -(CH2)- ;
    Z-A- est présent en position 2 ou 3, sur le noyau quinuclidine ;
    Z représente un groupe hydroxy, alkoxy en C1 à C6, NR1R2 ou W1-(CH2)m-CHR4-(CH2)n-NR3- dans lequel
    R1 et R2, lorsqu'ils sont pris séparément, représentent chacun l'hydrogène ou un groupe alkyle en C1 à C6 ;
    R1 et R2 lorsqu'ils sont pris conjointement avec l'atome d'azote auquel ils sont fixés, représentent un groupe pipéridino, pyrrolidino, morpholino, thiomorpholino ou pipérazino ;
    R3 représente l'hydrogène, un groupe alkyle en C1 à C6, benzyle ou -(CH2)r-W2 ;
    R4 représente l'hydrogène ou un groupe alkyle en C1 à C6 qui peut être substitué avec des substituants hydroxy, amino, méthylthio, mercapto, benzyle, 4-hydroxybenzyle, 3-indolylméthyle ou -(CH2)s-W3 ;
    R3 et R4 lorsqu'ils sont pris conjointement, représentent un groupe CH2 ou CH2CH2 ;
    W1, W2 et W3 représentent chacun un groupe cyano, hydroxyméthyle, alkoxyméthyle en C2 à C6, aminométhyle, mono (alkylamino en C1 à C6)méthyle, di(alkylamino en C1 à C6)méthyle, carboxyle, mono(alkyle en C1 à C6)carbamoyle, ou di(alkyle en C1 à C6)carbamoyle, carbamoyle ou (alkoxy en C1 à C6)carbonyle ; et
    m, n, r et s sont chacun égaux à 0, 1, 2 ou 3.
  2. Composé suivant la revendication 1, dans lequel Ar1 et Ar2 représentent chacun un groupe phényle.
  3. Composé suivant la revendication 2, dans lequel Z-A- est présent en position 3 ; et A représente un groupe -CO-.
  4. Composé suivant la revendication 3, dans lequel Z représente un groupe -OH, -OCH3, ou -NR1R2, dans lequel R1 et R2 représentent chacun -H, un groupe -CH3 ou CH2CH3.
  5. Composé suivant la revendication 4, dans lequel X représente l'hydrogène, un groupe 3-CH3, 3-CF3 ou 3-F ; et Y représente un groupe 5-CH3, 5-CF3 ou 5-F.
  6. Composé suivant la revendication 5, dans lequel Z représente un groupe -OH.
  7. Composé suivant la revendication 6, dans lequel X représente un groupe 3-CF3 et Y représente un groupe 5-CF3 ou bien X représente un groupe 3-CH3 et Y représente un groupe 5-CH3.
  8. Composé suivant la revendication 5, dans lequel Z représente un groupe -NH2 ou morpholino ; X représente l'hydrogène, un groupe 3-CF3, 3-CH3 ou 3-F ; et Y représente un groupe 5-CF3, 5-CH3 ou 5-F.
  9. Composé suivant la revendication 3, dans lequel Z représente un groupe NH2COCH2NH- ; X représente l'hydrogène, un groupe 3-CF3, 3-CH3 ou 3-F ; et Y représente un groupe 5-CF3, 5-CH3 ou 5-F.
  10. Composé suivant la revendication 2, dans lequel Z-A- est présent en position 3 ; A représente un groupe -(CH2)- ; Z représente un groupe OH ; X représente l'hydrogène, un groupe 3-CF3, 3-CH3 ou 3-F ; et Y représente un groupe 5-CF3, 5-CH3 ou 5-F.
  11. Composé suivant l'une quelconque des revendications 1 à 10, dans lequel la stéréochimie est la stéréochimie 3S,4R,5S,6S ou 3R,4S,5S,6S.
  12. Composé suivant la revendication 1, qui consiste en l'un des suivants :
    (3S,4R,5S,6S)-N-carbamoylméthyl-6-diphénylméthyl-5-(3,5-bis(trifluorométhyl)benzyloxy)-1-azabicyclo[2.2,2]octane-3-carboxamide ;
    (3S,4R,5S,6S)-6-diphénylméthyl-5-(3,5-bis(trifluorométhyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide ;
    (3S,4R,5S,6S)-N,N-(3-oxa-1,5-pentylène)-6-diphényl-méthyl-5-(3,5-bis(trifluorométhyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide ;
    acide (3S,4R,5S,6S)-6-diphénylméthyl-5-(3,5-diméthylbenzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylique ;
    (3S,4R,5S,6S)-N,N-diéthyl-6-diphénylméthyl-5-(3,5-bis(trifluorométhyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide ;
    acide (3S,4R,5S,6S)-6-diphénylméthyl-5-(3-fluoro-5-trifluorométhylbenzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylique ;
    acide (3S,4R,5S,6S)-6-diphénylméthyl-5-(3,5-bis(trifluorométhyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylique ; et
    (3S,4R,5S,6S)-N,N-diméthyl-6-diphénylméthyl-5-(3,5-bis(trifluorométhyl)benzyloxy)-1-azabicyclo[2.2.2]-octane-3-carboxamide.
  13. Utilisation d'un composé de formule (I) répondant à la définition suivant la revendication 1, ou d'un de ses sels pharmaceutiquement acceptables dans la production d'un médicament destiné au traitement ou à la prévention d'un trouble gastro-intestinal, d'un trouble du système nerveux central, d'une maladie inflammatoire, de l'asthme, de la douleur, de la migraine, des vomissements, de l'incontinence urinaire, ou de l'angiogénèse.
  14. Composition pharmaceutique destinée à antagoniser la substance P chez un mammifère, qui comprend une quantité thérapeutiquement efficace d'un composé suivant la revendication 1 ou d'un de ses sels pharmaceutiquement acceptables conjointement avec un support pharmaceutiquement acceptable.
  15. Composition pharmaceutique pour le traitement de troubles gastro-intestinaux, de troubles du système nerveux central, de l'allergie, de maladies inflammatoires, de l'asthme, de la douleur, de la migraine, des vomissements, de l'incontinence urinaire, ou de l'angiogénèse chez un mammifère, qui comprend une quantité thérapeutiquement efficace d'un composé suivant la revendication 1 ou d'un de ses sels pharmaceutiquement acceptables avec un support pharmaceutiquement acceptable.
  16. Composé de formule :
    Figure 00480001
    dans laquelle
    Ar1 et Ar2 représentent chacun un groupe aryle ou hétéroaryle, groupe qui est facultativement substitué avec un halogène ;
    A représente un groupe -CO- ou -(CH2)- ;
    T-A- est présent en position 2 ou 3 sur le noyau quinuclidine ;
    T représente un groupe hydroxy, alkoxy en C1 à C6, NR1R2 ou benzyloxy facultativement substitué avec un ou deux substituants choisis entre des substituants alkyle en C1 à C6, alkoxy en C1 à C6 ; et alkyle en C1 à C6 ; halogénosubstitué ;
    R1 et R2, lorsqu'ils sont pris séparément, représentent chacun l'hydrogène ou un groupe alkyle en C1 à C6 ; et
    R1 et R2 lorsqu'ils sont pris conjointement avec l'atome d'azote auquel ils sont fixés, représentent un groupe pipéridino, pyrrolidino, morpholino, thiomorpholino ou pipérazino.
  17. Composé suivant la revendication 16, dans lequel A représente un groupe -CO- ; et T représente un groupe NR1R2.
  18. Composé suivant la revendication 16, dans lequel A représente un groupe -CO- ; et T représente un groupe alkoxy en C1 à C6 ; ou benzyloxy facultativement substitué avec un ou deux substituants choisis entre des substituants alkyle en C1 à C6 ; et alkoxy en C1 à C6.
  19. Composé suivant la revendication 17 ou 18, dans lequel la stéréochimie est la stéréochimie 3S,4R,5S,6S.
  20. Procédé pour la préparation d'un composé suivant la revendication 17, qui comprend les étapes consistant :
    (a) à soumettre un composé de formule :
    Figure 00490001
    à une amidation pour obtenir un composé de formule :
    Figure 00500001
    et ensuite
    (b) à réduire le composé (ii) en présence d'un agent réducteur.
  21. Procédé pour la préparation d'un composé suivant la revendication 18, qui comprend les étapes consistant :
    (a) à réduire, en présence d'un agent réducteur, un composé de formule :
    Figure 00500002
    pour obtenir un composé de formule :
    Figure 00500003
    et ensuite
    (b) à soumettre le composé (vii) à une estérification.
  22. Procédé pour la préparation d'un composé suivant la revendication 1, qui comprend les étapes consistant :
    (a) à faire réagir un composé de formule :
    Figure 00510001
    avec un agent de benzylation pour obtenir un composé de formule :
    Figure 00510002
    (b) à hydrolyser ou réduire le composé (ix) pour obtenir un composé de formule :
    Figure 00510003
    et, si cela est désiré
    (c) à transformer le groupe carboxyle ou le groupe hydroxyméthyle du composé (vi) en un groupe désiré.
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US5869499A (en) 1999-02-09
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